DHEA and response to antidepressant treatment: A Mendelian Randomization analysis

Area of Science:

• Genetics and Psychiatry
• Endocrinology and Mental Health

Background:

• Predicting antidepressant treatment response and understanding its mechanisms remain challenging.
• Lower dehydroepiandrosterone sulphate (DHEA(S)) levels have been linked to depression and reduced antidepressant response, but causality is unclear due to potential confounding and reverse causation.

Purpose of the Study:

• To investigate the causal relationship between genetically predicted dehydroepiandrosterone sulphate (DHEA(S)) levels and response to antidepressant treatment using Mendelian randomization.

Main Methods:

• A two-sample Mendelian randomization (MR) analysis was conducted.
• Utilized the largest publicly available Genome-Wide Association Study (GWAS) data for DHEA(S) levels (n=14,846) with eight genetic variants.
• Employed various MR methods (IVW, MR Egger, Weighted mean, Weighted mode, MR-PRESSO) and single-nucleotide polymorphism (SNP) analysis on GWAS data for antidepressant response (n=5,218).

Main Results:

• No significant causal association was found for the DHEA(S) gene risk score across all MR methods.
• Individual variant analysis revealed significant associations for SNPs rs11761538, rs17277546, and rs2497306.
• Evidence of heterogeneity and pleiotropy was observed, suggesting complex underlying genetic effects.

Conclusions:

• This study provides preliminary evidence suggesting a potential causal link between genetically predicted dehydroepiandrosterone (DHEA) and improvement in depressive symptoms.
• The observed effect does not appear to be a simple linear relationship.
• Further research with refined instrumental variables is needed to elucidate whether the effect is direct, mediated by DHEA(S), or involves other pathways.